A process as indicated above has been known from WO 96/09056, which teaches wet granulation as a method of making dosage units comprising low doses of desogestrel or Org 30659. This known process leads to an excellent product stability. However, in the case of Org 30659, it leaves room for improvement as regards content uniformity.
An insufficient content uniformity, i.e. the situation that not all of the dosage units have the same quantity of the active substance, is a problem frequently incurred when making dosage units of potent steroids, which are micronised and which require low doses only (Org 30659 being in the range of from 0.005 to 1.0 % by weight and preferably of from about 0.01 to 0.5 percent by weight of each pharmaceutical dosage unit). Such potent compounds do not always distribute entirely evenly throughout, e.g., a tableting mixture, which may result in some of the tablets having relatively high amounts of steroid (i.e. "superpotent tablets"), while others have very low amounts of steroid. The content uniformity required in order to make a product in compliance with the US Pharmacopoeia should be such that the relative standard deviation of the content of the active substance (RSD) is below 6%. This in order to produce discrete dosage units which are reliable as a vehicle to administer a minute quantity of the active substance with a high accuracy. In terms of validated evidence (i.e. the requirement in the pharmaceutical industry that by validation of processes and products it is warranted that each dosage unit contains an adequate amount of the active substance), it is desired in the industry to strive for a higher degree of homogeneity, and to maintain an even stricter limit, e.g. an RSD of below 3%. This is also desirable for the sake of the practical feasibility of manufacturing the dosage units at an industrial scale. For, it is important to strictly adhere to as low an RSD as possible and to have as few as possible occasional batches with an RSD above 6%. This to avoid having to reject batches containing expensive and medicinally active substances, as such a waste of material is undesirable for both economical and safety and health reasons.
Another important aspect related to content uniformity, is that of the Demixing Potential (DP) of the granulate. This parameter is determined by screening the granulate so as to obtain different granule size sieve fractions (for example nine fractions, ranging from &lt;75.mu.m to &gt;800.mu.m particle size), and determining the content of said sieve fractions as a percentage of the declared content of the granulate. The DP is 0 if all of the fractions are in compliance with the declared content, i.e., if they all have a content of 100% of the declared content. The concept and determination of DP is known in the art, see e.g. EP 503 521. The lower the DP value, the better, as a granulate with a low DP below 15% and preferably below 10%, clearly is not prone to exhibiting segregation and will hence yield dosage units having a good content uniformity.
When Org 30659 is processed into a granulate using the known process, employing conventional high shear granulation apparatus, the DP typically is of the order of 30-40%. According to the invention it has now been found that, surprisingly, this figure, as well as the content uniformity of the granulate and the resulting dosage units, can be substantially improved.